Methoxsalen (or Xanthotoxin, 8-methoxypsoralen) sold under the brand name Oxsoralen among others, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

eczema Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...

vitiligo Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...

, and some cutaneous lymphomas in conjunction with exposing the skin to

ultraviolet Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...

(UVA) light from lamps or sunlight. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up the disease. Levels of individual patient PUVA exposure were originally determined using the

Fitzpatrick scale The Fitzpatrick scale (also Fitzpatrick skin typing test; or Fitzpatrick phototyping scale) is a numerical classification schema for human skin color. It was developed in 1975 by American dermatologist Thomas B. Fitzpatrick as a way to estimate t ...

. The scale was developed after patients demonstrated symptoms of

phototoxicity Phototoxicity, also called photoirritation, is a chemically induced skin irritation, requiring light, that does not involve the immune system. It is a type of photosensitivity. The skin response resembles an exaggerated sunburn. The involved chem ...

after oral ingestion of methoxsalen followed by PUVA therapy. Chemically, methoxsalen is a derivative of

psoralen Psoralen (also called psoralene) is the parent compound in a family of naturally occurring organic compounds known as the linear furanocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered a ...

and belongs to a class of organic natural molecules known as

furanocoumarin The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutacea ...

s. They consist of

coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by an unsaturated lactone ring , forming a second six-me ...

annulated with

furan Furan is a Heterocyclic compound, heterocyclic organic compound, consisting of a five-membered aromatic Ring (chemistry), ring with four carbon Atom, atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as f ...

. It can also be injected and used topically.

Natural sources

In 1947, methoxsalen was isolated (under the name "ammoidin") from the plant ''

Ammi majus ''Ammi majus'', commonly called bishop's flower, false bishop's weed, laceflower, bullwort, etc., is a member of the carrot family Apiaceae. The plant, which has white lace-like flower clusters, has a large distribution through Southern Europe, ...

'', bishop's weed. In 1970, Nielsen extracted 8-methoxypsoralen from four species of the genus '' Heracleum'' in the carrot family

Apiaceae Apiaceae () or Umbelliferae is a family of mostly aromatic flowering plants named after the type genus ''Apium,'' and commonly known as the celery, carrot, or parsley family, or simply as umbellifers. It is the 16th-largest family of flowering p ...

, including ''

Heracleum mantegazzianum ''Heracleum mantegazzianum'', commonly known as giant hogweed, is a monocarpic perennial herbaceous plant in the carrot family Apiaceae. ''H. mantegazzianum'' is also known as cartwheel-flower, giant cow parsley, giant cow parsnip, or hogsb ...

'' and ''

Heracleum sphondylium ''Heracleum sphondylium'', commonly known as hogweed or common hogweed, is a herbaceous perennial plant in the carrot family Apiaceae, which includes fennel, cow parsley, ground elder and Heracleum mantegazzianum, giant hogweed. It is native to m ...

''. An additional 32 species of the genus ''Heracleum'' were found to contain 5-methoxypsoralen (

bergapten Bergapten (5-methoxypsoralen) is a naturally-occurring organic chemical compound produced by numerous plant species, especially from the carrot family Apiaceae and the citrus family Rutaceae. For example, bergapten has been extracted from 24 ...

) or other

Biosynthesis

The biosynthetic pathway is a combination of the

shikimate Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower ''shik ...

pathway, which produces

umbelliferone Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and ''beta''-umbelliferone, is a natural product of the coumarin family. It absorbs ultraviolet light strongly at several wavelengths. There are some indications that this c ...

, and the

mevalonate pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...

Synthesis of umbelliferone

Umbelliferone is a

phenylpropanoid The phenylpropanoids are a diverse family of organic compounds that are biosynthesized by plants from the amino acids phenylalanine and tyrosine in the shikimic acid pathway. Their name is derived from the six-carbon, aromatic phenyl group and ...

and as such is synthesized from

L-phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...

, which in turn is produced via the shikimate pathway. Phenylalanine is lysated into

cinnamic acid Cinnamic acid is an organic compound with the formula phenyl, C6H5-CH=CH-Carboxylic acid, COOH. It is a white crystalline compound that is slightly soluble in water, and freely soluble in many organic solvents. Classified as an unsaturated carboxy ...

, followed by

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

cinnamate 4-hydroxylase In enzymology, a trans-cinnamate 4-monooxygenase () is an enzyme that catalyzes the chemical reaction :trans-cinnamate + NADPH + H+ + O2 \rightleftharpoons 4-hydroxycinnamate + NADP+ + H2O The 4 substrates of this enzyme are trans-cinnamate, N ...

to yield 4-coumaric acid. The 4-coumaric acid is again hydroxylated by cinnamate/coumarate 2-hydroxylase to yield 2,4-dihydroxy-cinnamic acid ( umbellic acid) followed by a bond rotation of the unsaturated bond adjacent to the

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

group. Finally an intramolecular attack from the hydroxyl group of C2' to the carboxylic acid group closes the ring and forms the

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

umbelliferone.

Synthesis of methoxsalen

The biosynthetic route then continues with the activation of

dimethylallyl pyrophosphate Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...

(DMAPP), produced via the mevalonate pathway, to form a carbo-cation via the cleavage of the diphosphates. Once activated, the enzyme umbelliferone 6-prenyltransferase catalyzes a C-alkylation between DMAPP and umbelliferone at the activated position ortho to the phenol, yielding demethylsuberosin. This is then followed by a hydroxylation catalyzed by the enzyme marmesin synthase to yield

marmesin Marmesin (nodakenetin) is a chemical compound precursor in psoralen and linear furanocoumarins biosynthesis. Marmesin plays a central role in the biosynthesis of furocoumarins in the plant ruta graveolens, more commonly known as rue. It acts as ...

. Another hydroxylation is catalyzed by

psoralen synthase In enzymology, a psoralen synthase () is an enzyme that catalyzes the chemical reaction :(+)-marmesin + NADPH + H+ + O2 \rightleftharpoons psoralen + NADP+ + acetone + 2 H2O The 4 substrates of this enzyme are (+)-marmesin, NADPH, H+, and O2 ...

to yield

. A third hydroxylation by the enzyme psoralen 8-monooxygenase yields xanthotoxol which is followed by a methylation via the enzyme xanthotoxol O-methyltransferase and

S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur thro ...

to yield methoxsalen.

Risks and side effects

Patients with

high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...

or a history of

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

problems are at risk for inflammation and irreparable damage to both liver and skin. The eyes must be protected from UVA radiation. Side effects include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, and in rare cases

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

. Methoxsalen has also been classified as an IARC Group 1 carcinogen (known to cause cancer) but is only cancerous when combined with light - UVA radiation.

Society and culture

Author John Howard Griffin (1920–1980) used the chemical to darken his skin in order to investigate racial segregation in the American South. He wrote the book ''

Black Like Me ''Black Like Me'', first published in 1961, is a nonfiction book by journalist John Howard Griffin recounting his journey in the Deep South of the United States, at a time when African-Americans lived under racial segregation. Griffin was a na ...

'' (1961) about his experiences.

References

{{Portal bar , Medicine CYP1A2 inhibitors CYP3A4 inhibitors Photosensitizing agents IARC Group 1 carcinogens Furanocoumarins O-methylated coumarins Catechol ethers General cytochrome P450 inhibitors Orphan drugs Plant toxins